The Microbiome Congress in May in Rotterdam brought together three conferences: the 6th Microbiome forum, the 3rd Probiotics Congress and the Skin Microbiome and Cosmeceuticals congress, running in parallel. For this reason this report can’t be exhaustive and we apologize to speakers we were not able to include.
Skin Microbiome and Skinbiotics
Bernhard Paetzold, CSO at S-Biomedic gave a mind-opening talk about the physiological importance of Cuticubacterium acnes. If the body leaves it alone, he says, it must be an important species. Indeed, C. acnesis the most abundant bacterium on our face, and the protein it most secretes is a strong anti-oxidant. Against acne, the usual bleach-based treatment should be followed by application of a high count of neutral C. acnesto occupy the niche, avoiding the pathogen’s regrowth, and supporting skin health with anti-oxidants and hydration. In an open-label pilot with 14 participants, the 5 weeks bacteria application after one week on BPO led to significantly reduced total lesion counts and non-inflamed lesion counts, with participants reporting less oily skin and less visibile pimples.
“Believe in probiotics rather than prebiotics on the skin, because you want to control who you are going to boost”.
Anneleen Cornelissen presented the German company Lysando’s novel antibacterial technology platform called Artilysin®. Very positively charged redesigned peptidoglycans destabilize and destroy Gram+ bacteria. The technology allows a targeted action and doesn’t provoke resistance nor irritation. In the context of growing antimicrobioal resistance, this is an important novelty and it has broad implications for the skin microbiome, in wound healing, body odour, atopic dermatitis, acne, psoriasis and rosacea to name a few.
The President and CEO of AOBiome Todd Krueger shared the challenges faced and lessons learnt around the research, development, manufacturing and bringing to market of such a new family and concept that is behind the company’s ammonia-oxidizing bacteria, and their position sitting between cosmetics and drugs (relating to the Regulatory Hurdles panel discussion).
Maya Ivanjesku, CSO at LaFlore Skin Care, animated a round table around the question of safety for live probiotic cultures used on the skin. Mostly, fear comes from not knowing, so an important topic is always the education of consumers. For their products, LaFlore evaluated the safety by the transient presence of the bacteria, confirmed by swabs, prior and post application. The objective is to target pathogens without harming commensals, so they can come back and keep the balance. Maya’s presentation during the Skin Microbiome and cosmeceuticals congress compared lysates to live bacteria for topical application. The benefit of live bacteria is their continuous production of metabolites on the skin, including Short Chain Fatty Acids (SCFA) and lactic acid (postbiotics) able to nourish the skin. Interestingly, there is a discrepancy between science and regulation: cosmetic companies have to label generic INCI names (Hansenula, Lactobacillus, Lactococcus, etc.) whichever be the strain-specific data generated by the company. The question of stability within a formula that requires preservatives is also a major one for this industry, that needs to select with care the preservatives and the know-how to protect/encapsulate the probiotics.
Kristin Neumann, founder of MyMicrobiome, introduced the internet platform that aims to set new standards and a quality seal in the microbiome cosmetics industry, enabling approved companies to claim “Microbiome friendly” with a rating. The quality check consists in the product resulting in a decrease of S. aureus on the skin, and products that don’t contain probiotics, prebiotics or postbiotics are also welcome to be tested. The tool is completed by a website to raise more awareness: https://www.mymicrobiome.info/welcome.html.
Probiotics: research in gastrointestinal health
Herman Van Wietmarschen from Winclove presented results of a study in a nursing home in which patients treated with antibiotics also received a probiotic blend, Ecologic® AAD. The occurrences of antibiotic associated diarrhea (AAD) dropped from 36 to 20%. The group learnt that implementing such a protocol in a nursing home requires an enthusiastic medical team, adding the probiotic to the medicines list as standard care, and some teaching on how to administer it.
Ger Rijkers, Professor at University College Roosevelt in Netherlands, offered a fantastic review on probiotics efficacy to counteract side effects of antibiotic treatments. Side effects of neonatal antibiotic treatment for 7 days increased wheezing (from 30 to 42,2%) and colics (from 14,4 to 24,8%). Martin Blaser also reported increased risks of developing Inflammatory Bowel Diseases (IBD) after antibiotic treatments, not to mention obesity. Ger Rijkers however focused on AAD and his meta-analysis concluded on the recommendation to take 2 billion cfu per day of L. rhamnosus GG during and after antibiotics intake.
Wendy Dahl, associate Professor at the University of Florida presented results on B. lactis B94 from Lallemand on gastrointestinal symptoms in adults with Prader-Willi syndrome, a genetic disorder leading to hyperphagia and obesity, and associated with bloating, constipation, diarrhea and reflux. The group studied 26 adults in residential care who were supplemented for 4 weeks with the probiotic or a placebo, then washed out and crossed over. Some clinical results were found in some individuals, though not overall, mostly because not all participants were constipated at baseline. Indeed, the most constipated benefitted the most from the probiotic.
Gut microbiota and probiotics in vaginal health, pregnancy and infancy
Mariya Petrova from the University of Antwerp and founder of Microbiome Insights and Probiotics Consultancy, explained molecular-based mode of action of L. rhamnosus GR-1 for adhesion, pathogen exclusion and immunomodulation. She compared the genomes of L. rhamnosus GR-1 isolated from the vagina, L. rhamnosus GG originating from the gut, and L. rhamnosus 705, derived from dairy. Out of about 2 300 genes, 270 are unique to GG, 118 unique to 705 and 48 to GR-1. Probably GR-1 makes its way more easily to the vaginal niche because it doesn’t have the tools to bind to the gut epithelium. However, not adapted to survive digestion, it doesn’t survive well to the GI tract and if delivered orally, it should be well protected.
Omry Koren of Bar-Ilan University in Iran showed what changes occur to the gut microbiome during pregnancy and infancy. 400 pregnant women from Isreal confirmed results already described in a Finnish cohort: the microbiome shifts during the Third Trimester of pregnancy, with a decrease in species richness and an increase of Proteobacteria and Actinobacteria, including a very significant increase in Bifidobacteria (possibly selected during the course of evolution to increase chances of transmission to the newborn). Pregnancy’s “dysbiosis” is a healthy change however, as we observe more complications when this reaction doesn’t occur. At early age the microbiome is characterized by less stability and more disturbances. Antibiotic treatments caused long term changes – for example penicillin caused disappearance of some species that after 2 years of follow-up still hadn’t come back.
Gut microbiota and probiotics in metabolic, cardiovascular health, weight and fatty liver disease
- A probiotic for weight management
Gregory Lambert, CEO of Targedys, described the technology behind the French recently-launched Enterosatys, dietary supplement for increased satiety that just won a NutraIngredients Award. Since the discovery of ghrelin antibodies in obese population, the hypothesis was raised that eating disorders could have autoimmune origin. The researchers demonstrated the molecular mode of action of the strain, based on Caseinolytic peptidase B protein (ClpB), to reduce hunger, food intake, body weight and glycemia. They isolated the bacterium Hafnia alvei from raw milk cheese: Tim Spector’s intuition that the French paradox could come from the bacterial diversity of raw milk cheese is starting to prove right! Camembert delivers 106cfu/g of the Enterobacteriacea– while the product delivers 109, and the company optimized fermentation for a 100-fold production of ClpB. 22 publications characterize the mode of action and benefits in mice and a clinical study is now on-going with 230 subjects. So far 72% declared feeling improved satiety and 85% would recommend the product. Targedys also works on ProbioNutrys aiming to mimick ghrelin in order to stimulate appetite in seniors with sarcopenia, and the team is looking for distributors to deploy the product in EU and US.
- FMT in metabolic syndrome
Jos Seegers from Caelus Health presented studies demonstrating the potential of Fecal Microbiome Transplant (FMT) in cardiovascular health. A double-blind placebo-controlled (with autologous FMT) randomized controlled trial (RCT) in patients with metabolic syndrome showed good results on glucose levels and insulin resistance, with significant changes in whole body hormone sensitivity. Beneficial changes of the microbiota in the small intestine were also observed, with an increase in butyrate-producer E. hallii. Importantly, there is variability in the impact of FMT, and the compatibility between donor and receptor microbiomes appears crucial for the pratice’s success. Donors are deeply screened and characterized both for safety and for a better understanding and predictability of this compatibility. FMT is able to substantially modify the production of SFCA, TMAO, PYY, TG, vitamins, neurotransmitters and a number of other peripheral products having an impact on the whole metabolism.
- Metbolomics and Fatty liver disease
Fatty liver disease is mostly linked to metabolic syndrome, quickly increasing with the obesity epidemic, and now affects up to 23% of people in Europe. Lesley Hoyles, Associate Professor at Nottingham Trent University, explored the role of the gut microbiome in Non-Alcoholic Fatty Liver Disease (NAFLD). Microbiomics consistently show that NAFLD patients are characterized by an increase in Escherichia and Proteobacteria, and a decrease in Coprococcus and gene count (microbial richness). These variations are associated with a different aminoacid profile, with excess Leucin, Valin, Isoleucin and Phenylacetate, which causes hepatic lipid accumulation. The work on metabolomics is now repeated on over 700 individuals with the objective of using the metabolome as a rapid and cheaper diagnostic tool.
The Blood Microbiome
After polemics on the existence of the breastmilk, placental and the bladder microbiomes, it is now the turn to the blood microbiome to be finally described. Benjamin Lelouvier, CSO of Vaiomer, fought for 2 years together with his team of 10 people, to make it feasible to analyse and identify blood bacteria by PCR and 16s. In the blood, over 80% of bacteria is Proteobacteria, and there is a small quantity of Actinobacteria. Some are viable, some are dormant, some in L-forms: wall-free, they can divide but can’t be cultivated from blood. Consistently with Lesloy Hoyles’ findings, people with liver steatosis showed a clear surge in Proteobacteria DNA in the blood. Acute coronary syndrome also increases bacterial DNA in the blood. The group would like to study more in-depth the blood microbiome, variability between individuals and intra-individual during the day, and evaluate its predictive power of infections and diseases.
Probiotics and the nasal microbiome in Respiratory Tract Infections (RTIs)
Markus Lehtinen, principal scientist in DuPont, looked at the nasal microbiota and the role of selected probiotics for preventing RTIs. B. lactis BL04, dosed at 2 billion cfu/day in 310 healthy subjects significantly decreased the risk of RTI (RR 27%, hazard ratio 0.73). Another RCT with the strain at the same dosage and with a rhinovirus challenge found that BL04 was present in 10% of the subject’s nasal swabs, that the nasal microbiome was quite stable, even during the time of infection, and that the nasal virus load was significantly lower in the probiotics groups, though BL04 didn’t affect symptom severity.
Probiotics in the gut-brain axis
Paul Forsythe from the Brain-Body Institute of McMaster University, Canada, studies psychoneuroimmunology, that is the interaction between the brain, neural functions and immune processes. Mice gavaged with L. rhamnosus JB-1 showed less anxiety (in Openfield) and depression (in the tail suspension test). The brain chemistry responds to the bacterium very quickly and the behavioral effects appear to be mediated by the vagus nerve. JB-1 increases vagal firing frequency (p<0,0001) – just the same as SSRI antidepressants! Another pathway for influence of JB-1 on mood is through the interaction with dendritic cells in the small intestine, inducing Tregs to suppress inflammation thanks to CD25 antibodies – thus decreasing anxiety and depression. Paul thinks these results could translate to an anxious human population.
Novel technologies supporting innovation in research, quality and production
Biomillenia, Biotech based near Paris, sources and screens novel microbes thanks to a high throughput technology platform to test relevant characteristics of miroorganisms. The company’s CEO Dirk Loffert explained how oil droplets are interrogated by chips for enzymatic activities or binding assays, with over 30 million clonal microbe populations a day. Microbes can be grown in different media and conditions at the same time, optimizing upscale possibilities.
Josipa Dragun, scientist at ForteBio, also proposes technological solutions and lab instruments to accelerate the selection and characterization of clones for biologics development and automatize laboratory work and efficacy.
Heloise Breton from DNA Genotek described the recently acquired synergies with CoreBiome for an optimized workflow and custom analyses in advanced bioinformatics, and the company is committed to go the extra mile to solve logistical challenges.
Tingting Zhou, General Manager at Novogene, presented the giant company specialties. Focused on cutting-edge genome technologies to improve human healthcare, Novogene is the largest sequencer in the world, counting over 1 600 employees globally, over 37 000 projects and running 280 000 Whole Genome Sequencing analyses per year.
Christophe Lacroix, Professor in ETH Zurich, provided insight on novel technologies to produce strict anaerobes. Continuous culture has its benefits (yield) and limits (genetic drift). Beads of polysaccharide matrixes can model the intestine and provide possibility to grow and stabilize consortia. Prof. Lacroix’s experience shows that co-culture increases productivity by 54%. Which raises the question of regulatory hurdles for registration of consortia as Live Biotherapeutic Products (LBPs).
Stefania Arioli, Post-Doc in Milan, suggested Omics-Based Quality Control for multi-strains probiotic formulations. Using the example of VSL#3, she checked the compliance of identity, safety (antibiotic resistance genes), certain enzymatic activities (betagalactosidase, urease) and metaproteomic characterization (identification of 1800 proteins, assigned to the 7 species). She also looked at viability as a major quality component, which was assessed by flow cytometry.
Sandra Robelet presented Syncrosome’s services and models to study the communication between gut microbes and other organs, and the mechanisms behind. Animal models are proposed all the way from digestive IBD, IBS, ulcer etc., to Parkinson, strokes and cardiovascular disorders, as well as asthma and bronchitis.
Regulatory Hurdles Panel Discussion
Asma Serier and Colette Shortt of J&J, Bernhard Paetzold of S-Biomedic and Eric De La Fortelle from Seventure Partners discussed the regulatory obstacles and questions sitting between discovery and market in the microbiome space. In the context of new complexities and of the digitalization of healthcare, there are big opportunities and challenges for pharmaceutical companies, often regarding the absence of a defined regulatory status for new types of therapeutics. Colette Shortt puts it this way
“The great thing about the Microbiome is it can fit in a wide array: drugs, medical foods, medical devices, cosmetics…”.
Early-on decision on the product status is important – and should be in line with the potential market, taking into account the variety of regulations. Canada for example has a unique approach to microbes with Natural Health products and well-defined monographs. Paetzold highlighted the challenge for a small start-up that can’t dedicate a full-term person to work on product status, nor can climb the wrong mountain, and was grateful for J-Labs services to support with the regulatory know-how to get to market. Similarly Seventure helps orientate companies define whether their products should fall under food supplements, drug or cosmetics. “Focus is a good thing”. However, Bernhard advises,
“If you can cannibalize your business model, then you should do it – otherwise somebody else will”.
Probiotics and the microbiome: challenges and responsibilities in education
Bruno Pot argued that getting consumers correctly informed on probiotics is a responsibility shared between Industry, Regulators and the Press. Nutrition is an area that generally faces controversies that science is not able to definitively settle (cf. butter, cholesterol and meat). Relations to health and the environment are complex and social media participate in oversimplifying the messages. Articles like the Brain Fogginess (Rao et al., 2018) received 385 000 views in a few days though lacking background information. Bruno urges the players for the following:
- For the Industry to keep investing in high quality research, and not confuse consumers with false promises.
- For the Researchers to be independent, use established technologies and publish in peer-reviewed, high impact Journals.
- For the Media to take time to verify information, communicate in a balanced, non-skewed way on new research, and bloggers to refrain from commenting outside of their expertise.
- For Regulators to define feasible criteria, clarify status, publish a Codex on probiotics and define appropriate levels of evidence for safety and functionality.
- For Governments to encourage new product development, control the compliance of probiotics and police “cowboy products”.
- For consumers to stay realistic with regards to dietary supplements, to be critical towards the information received, and to be informed and responsible with their nutrition.
In the Panel “Moving Probiotics Forward”, the main idea was also to keep doing good science. Annick Mercenier, CIO at Nutrileads and strong of a career with Institut Pasteur and Nestlé, wisely reminded:
“We’re in the euphoric phase. We generalize too much and our responsibility is to be humble and recognize what we don’t know. Mechanistical explanations are important, but we should also acknowledge that bacteria carry multiple effects and produce multiple molecules, so focusing on one target pathway doesn’t give the full picture and impact”.
Many foods help many people be healthy but there’s no one food that will keep everybody healthy, and the same is true for probiotics: variability exists in foods, drugs, food supplements and probiotics alike. The problem is oversimplification of the message, such as ads stating “it protects my microbiome”, while we still don’t know what is a healthy microbiome. The panel encourages to communicate more to Healthcare professionals than to the Press, but also as advised by Soren Kjaerulff, CEO of Lactobio, to work more on the Press release than on the scientific article. Bruno Pot concludes:
“maybe we have too many scientists and not enough communicators”
Before entering industry, Nina was involved in human nutrition research at Penn State University, USA, the French National Center for Scientific Research (CNRS) and the National Institute for Agronomic Research (now INRAe). She has an engineer degree from AgroParisTech, Paris Institute of Technology for Life, Food and Environmental Sciences. After over 6 years developing science-backed probiotic supplements sales across Europe for Probiotical, she is today international sales director for the French biotech TargEDys, the ambassador of precision probiotics.